Episode 76: Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors

**Monday Immune Engager** — our weekly pick from the latest immune-engager digest. **Paper:** [Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors](https://doi.org/10.1080/19420862.2026.2684378) **Authors:** Welbeck Danquah, Mélanie Pichery, Thomas Eden, Aurelien Boyance, et al. **Journal:** mAbs, 2026 **Why it matters:** CD3 T cell engagers have transformed blood cancer treatment but largely failed in solid tumors — this study proposes a modular two-drug strategy that separates T cell activation signals to rescue efficacy while dramatically reducing systemic toxicity. --- **Summary** CD3 T cell engagers (TCEs) work by bridging a T cell directly to a tumor cell, providing what immunologists call Signal 1. In blood cancers this is often sufficient, but solid tumors present an immunosuppressive microenvironment that demands a second costimulatory signal (Signal 2) for a sustained cytotoxic response. Pushing TCE doses higher to compensate triggers severe dose-limiting toxicities before the tumor is controlled — a bottleneck that has left tarlatamab as the only approved classical TCE for solid tumors. The Evotec team's solution is to keep the two signals as entirely separate drugs: a conventional EpCAM×CD3 TCE (solitomab) for Signal 1, and a novel HER2×CD2 bispecific for Signal 2. The CD2 arm is built on a non-blocking antibody that acts as a positive allosteric modulator — rather than competing with CD58, the tumor's natural CD2 ligand, it increases CD2–CD58 binding by over twofold, amplifying the natural immune adhesion while simultaneously providing artificial costimulation. The Fc domain is silenced to prevent macrophage-mediated depletion of CD2-expressing T cells. In humanized xenograft mice bearing established HER2-positive breast tumors, the combination achieved complete tumor remission in 8 of 9 animals at a TCE dose that produced remission in only 1 of 9 when used alone. Two additional findings underscore the approach's clinical relevance. First, when tumor cells were engineered via CRISPR-Cas9 to completely lack CD58 — mimicking a well-documented immune escape mechanism — the HER2×CD2 combination physically bridged the T cell to the tumor anyway, boosting TCE killing efficacy 25–35-fold over the TCE alone. Second, because CD28 expression is lost from a large proportion of CD8⁺ killer T cells with aging, CD28-targeted costimulatory strategies may be ineffective in the elderly patients who make up most solid tumor cases; CD2 expression remains robust on these cells. In a direct head-to-head comparison at matched killing efficacy, the CD2 bispecific induced only up to a 2-fold increase in IL-6, TNF, and IL-2, compared to up to a 200-fold increase from a comparable HER2×CD28 bispecific. --- **Three takeaways** 1. Adding the HER2×CD2 bispecific to a sub-efficacious low dose of an EpCAM×CD3 TCE restored full anti-tumor cytotoxicity in vitro (~10-fold improvement) and drove complete tumor remission in 8 of 9 humanized mice versus 1 of 9 with the TCE alone. 2. The CD2 combination overcame CD58 loss — a common tumor immune escape route — by physically forcing T cell–tumor contact, boosting TCE efficacy 25–35-fold against CD58-knockout cancer cells. 3. CD2 costimulation effectively engaged CD28-negative CD8⁺ T cells (the dominant cytotoxic subset in elderly patients and solid tumors) while triggering up to 200-fold less pro-inflammatory cytokine release than a matched-efficacy HER2×CD28 bispecific. --- **Read the source:** https://doi.org/10.1080/19420862.2026.2684378